US3079408A - Ig-bisoxygenated iy-haloestra- - Google Patents
Ig-bisoxygenated iy-haloestra- Download PDFInfo
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- US3079408A US3079408A US3079408DA US3079408A US 3079408 A US3079408 A US 3079408A US 3079408D A US3079408D A US 3079408DA US 3079408 A US3079408 A US 3079408A
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- Prior art keywords
- trien
- methoxyestra
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- bromo
- triene
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- 150000001875 compounds Chemical class 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 36
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 28
- 238000000034 method Methods 0.000 description 24
- -1 alkanoyl radicals Chemical class 0.000 description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 238000006467 substitution reaction Methods 0.000 description 12
- WGLPBDUCMAPZCE-UHFFFAOYSA-N trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 12
- 230000000875 corresponding Effects 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 150000005671 trienes Chemical class 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 229940117975 chromium trioxide Drugs 0.000 description 6
- 125000001475 halogen functional group Chemical group 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminium hydride Substances [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 description 6
- OCZDCIYGECBNKL-UHFFFAOYSA-N lithium;alumanuide Chemical compound [Li+].[AlH4-] OCZDCIYGECBNKL-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 150000003944 halohydrins Chemical class 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- UHDFDVNBHMUVOO-YRXWBPOGSA-N (8S,9S,13S,14S)-3-methoxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene Chemical compound C1C[C@]2(C)CCC[C@H]2[C@@H]2CCC3=CC(OC)=CC=C3[C@H]21 UHDFDVNBHMUVOO-YRXWBPOGSA-N 0.000 description 2
- JMSRBKPMLUGHCR-UHFFFAOYSA-N Bromohydrin Chemical class BrC[C]1CO1 JMSRBKPMLUGHCR-UHFFFAOYSA-N 0.000 description 2
- 210000000981 Epithelium Anatomy 0.000 description 2
- 229940011871 Estrogens Drugs 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N HF Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- XCRBXWCUXJNEFX-UHFFFAOYSA-N Peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 229940030484 SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM ESTROGENS Drugs 0.000 description 2
- 229960001124 Trientine Drugs 0.000 description 2
- VILCJCGEZXAXTO-UHFFFAOYSA-N Triethylenetetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004432 carbon atoms Chemical group C* 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000007269 dehydrobromination reaction Methods 0.000 description 2
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 2
- 229940046080 endocrine therapy drugs Estrogens Drugs 0.000 description 2
- 238000006345 epimerization reaction Methods 0.000 description 2
- 238000006735 epoxidation reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 229910000286 fullers earth Inorganic materials 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 239000008079 hexane Substances 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006011 modification reaction Methods 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000006864 oxidative decomposition reaction Methods 0.000 description 2
- FDJABJJEKWDNQO-UHFFFAOYSA-N pentane;propan-2-one Chemical compound CC(C)=O.CCCCC FDJABJJEKWDNQO-UHFFFAOYSA-N 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 229940094025 potassium bicarbonate Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000003638 reducing agent Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
Definitions
- the present invention relates to novel 17-halogenated steriods, and especially to 3,16-bisoxygenated 17-haloestra-1,3,5(10)-trienes, which can be represented by the structural formula (if; ROI I wherein R is selected from the group consisting of hydrogen, lower alkyl, and lower alkanoyl radicals; X is a halogen atom; and Z is selected from the group consisting of carbonyl, hydroxymethylene, and (lower alkanoyl) oxy-methylene radicals Lower alkyl radicals represented by R are exemplified by methyl, ethyl, propyl, butyl, pentyl, hexyl, and the branched-chain isomers thereof.
- the lower alkanoyl radicals encompassed by R and Z are, for example, formyl, acetyl, propionyl, butyryl, valeryl, caproyl, and the branched-chain isomers thereof; said groups being the acyl radicals of alkanoic acids containing fewer than 7 carbon atoms.
- Suitable starting materials for the manufacture of the instant compounds are the appropriately 3-oxygenated 16,17 epoxyestra 1,3,5 (10) trienes.
- Dehydrobromination of the 3-oxygenated l6a,175 -halohydrins prepared by the method disclosed at J. Org. Chem. 23, 1190 (1958), affords the 5-epoxides, as typified by the reaction of 16a-bromo-3-methoxyestra-1,3,5(10) trien-l75 01 With methanolic potassium hydroxide to afford 3-methoxy 165,l75-epoxyestra-1,3,5(l0) triene.
- reaction of these 5-epoxides with a hydrohalogen acid results in the instant l7a,-l65-halodydrins.
- reaction of the u-epoxides, prepared by epoxidation of the corresponding l6-dehydro derivatives with perbenzoic acid, with a hydrohalogen acid produces 175,l6cx-halohydrins of this invention.
- Oxidation of the aforementioned halohydrins typically with chromium trioxide in pyrid'ne, results in the corresponding 17-halo 16-ketones.
- the reaction of l7a-bromo-3-methoxyestra-1,3,5(10)-trien 165- 01 with chromium trioXide in pyridine affords 17a-bromo- 3-rnethoxyestra-l,3,5 10) -trien-l6-one.
- the 175-halo l6-ketones of this invention can be manufactured also by epimer-ization of the corresponding 17w halo compounds. This process is specifically illustrated by the reaction of 17d-bromo-3-methoxyestra 1,3,5(16)- trien-16-one with p-toluenesulfonic acid to afford 17abromo-3-methoxyestra-1,3,5(10)-trien-l6-one.
- the 16,17 epoxy-3-hydroxyestra-1,3,5(10)- trfenes can be used as such to achieve the instant 3-hydroxy compounds
- the phenolic moiety is preferably protected by a lower alkanoyl group in order to prevent any possible oxidative decomposition.
- 16a-bromo-3- hydroxyestra-1,3,5(10)-trien-l75-ol is reacted with methanolic potassium hydroxide to afford 165,175 epoxy-3- hydroxyestra-1,3,5(10)-triene, which is treated with a low er alkanoic ac'd anhydride in pyridine to afford the corresponding 3-(lower alkanoate).
- This ester can be, of course, treated as described in detail supra, to afford the 3-hydroxy compounds of this invention.
- the instant 3,16-di-(lower alkanoates) are preferably manufactured by reaction of the corresponding 3,16-diols with a lower alkanoi-c acid anhydride in pyridIne.
- a lower alkanoi-c acid anhydride in pyridIne As a specific example, 175 bromo-3-hydroxyestra-1,3,5(l0)- trien-l65-o1 is treated with acetic anhydride in pyridine to yield 3,165 diacetoxy 175-bromoestra 1,3,5(10)-' triene.
- the compounds of this invention are useful as result of the'r valuable pharmacological properties. They are, for example, estrogens in consequence of their ability to promote uterine growth and to produce characteristic changes in the vaginal epithelium.
- Example 2 To a solution of one part of 165,175-epoxy-3-methoxyestra-1,3,5(10)-triene in 38 parts of chloroform is added at 05, 15 parts of 48% aqueous hydrobromic acid, and the mixture stirred for about 5 minutes. The chloroform layer is separated, washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness in ('10)-trien-l6,6-ol. This bromohydrin displays an infra-' red maximum at 2.77 microns.
- Example 3 To a solution of one part of 163,17B-epoxy-3-methoxyestra-l,3,5(10)-triene in 38 parts of chloroform is added, at 0-5 24 parts of concentrated hydrochloric acid and the mixture shaken for about minutes. The chloroform layer is separated, washed with Water, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. The residue is extracted with ether and the extract clarified by centrifugation, then evaporated to dryness in vacuo to yield 17a-chloro-3-methoxyestra- 1,3,5 (10) -trien-l6 ⁇ 3-ol, which exhibits a maximum in the in irared at 2.77 microns.
- Example 4 To a suspension of 2.4 parts of chromium trioxide in 24 parts of pyridine is added, with stirring, a solution of 1.2 parts of 17wbromo-3-methoxyestra-1,3,5(10)-trien- 165-01 in 12 parts of pyridine. Stirring at room temperature is continued for about 3 hours, then water added and the mixture extracted with ether. The ether layer is separated, washed successively with water, dilute hydrochloric acid, water and saturated aqueous sodium chloride; then dried over anhydrous magnesium sulfate and concentrated to an oil in vacuo.
- Example 7 A mixture of 2 parts of 17a-bromo-3-methoxyestra-1, 3,5(l0)-trien-16-one, 5 parts of p-toluenesulfonic acid, and 100 parts of acetic acid is heated at reflux for about 68 hours. The reaction mixture is diluted with water and extracted with benzene. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness at reduced pressure. A benzene solution of the residue is chromatographed on silica gel.
- Example 9 To a stirred solution of 7 parts of lithium aluminum hydride in 700 parts of ether is added, at 5 over a period of several minutes, a solution of 15 parts of 175- bromo-3-methoxyestra-1,3,5(10)-trien-l6-one in 355 parts of tetrahydrofuran. The reaction mixture is treated successively with 50 parts of water and 10 parts of 10% aqueous sodium hydroxide, filtered through a bed of anhydrous magnesium sulfate containing a filter aid and evaporated to dryness at reduced pressure.
- Example 10 A mixture of one part of 17a-bromo-3-hydroxyestra- 1,3,5 (10)-trien-l6p-ol, 10 parts of acetic anhydride, and 20 parts of pyridine is warmed on the steam bath to achieve homogeneity, then allowed to stand at room temperature for about 16 hours. The reaction mixture is diluted with water and extracted with ether. The organic solution is washed successively with aqueous sodium bicarbonate and water, dried over anhydrous magnesium sulfate, and evaporated to dryness in vacuo to yield 3,16,8-diacetoxy-l7ot-bromoestra-l,3,5 (10)-triene.
- Example 11 A mixture of 2 parts of 17a-bromo-3-hydroxyestra- The benzene solu-.
- 1,3,5()-trien-16-one 10 parts of acetic anhydride, and 20 parts of pyridine is allowed to stand at room temperature for about hours.
- the reaction mixture is diluted with water and extracted with benzene.
- the organic layer is separated, washed successively with water and aqueous potassium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated to dryness in vacuo.
- the crude product can be recrystallized from aqueous ethanol to produce pure 3-acetoxy-l7a-brornoestra-1,3, 5(10)-trien-l6-one. This substance displays maxima in the infrared at 5.70 microns.
- Example 13 By substituting an equivalent quantity of 17/8-chlor0- 3-methoxyestra-1,3,S(10)-trien-l6-one and otherwise proceeding according to the procedure of Example 9, 17/8- chloro-3-methoxyestra-1,3,5(10)-trien-16fl-ol is obtained.
- Example 15 The substitution of an equivalent quantity of 17a:- bromo-3-methoxyestra-1,3,5 (10) trien 165 01 or 175- chloro-3-methoxyestra-1,3,5(10)-trien-16B-ol in the process of Example 10 results in l6fl-acetoxy-l7u-bromo-3- methoxyestra-l 3, 5 10)-triene and 16B-acetoxy-17/3-chloro-3-methoxyestra-1,3,5(10)-triene.
- Example 17 The substitution of an equivalent quantity of 17afiuoro-3-methoxyestra-1,3,5(10) trien 16,3 01 or 17 3- fluoro-3-methoxyestra-1,3,5(10)-trien-16ao1 in the procedure of Example 4 affords 17a-fluoro-3-methoxyestra- 1,3,5 (10)-trien-l6-one, M.P. about 148l49 and 17B-fiuoro-3-methoxyestra-1,3,5 (10)-trien 16 one, M.P. about -156, respectively.
- 17-bromo-3-methoxyestra-1,3,5 10) -trien-16-one 1 7-ch1oro'3-methoxyestra-1,3,5 10 -t.rien-1 6-one. 17-bromo-3-methoxyestra-1,3,5(10)-trien-l6-o1. 17-chloro-3-methoxyestra-1,3,5 10) -trien-1 6-01. 17-f1uoro-3-methoxyestra-1,3,5 10) -trien-16-one. 17-fiuoro-3-rnethoxyestra-1,3,5 10 -trien- 1 6-01.
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- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
United States Patent Oflice 3,979,498 Patented Feb. 26, 1953 No Drawing. Filed Apr. 17, 1961, Ser. No. 103,267 7 Claims. (Cl. 2i397.4)
The present invention relates to novel 17-halogenated steriods, and especially to 3,16-bisoxygenated 17-haloestra-1,3,5(10)-trienes, which can be represented by the structural formula (if; ROI I wherein R is selected from the group consisting of hydrogen, lower alkyl, and lower alkanoyl radicals; X is a halogen atom; and Z is selected from the group consisting of carbonyl, hydroxymethylene, and (lower alkanoyl) oxy-methylene radicals Lower alkyl radicals represented by R are exemplified by methyl, ethyl, propyl, butyl, pentyl, hexyl, and the branched-chain isomers thereof. The lower alkanoyl radicals encompassed by R and Z are, for example, formyl, acetyl, propionyl, butyryl, valeryl, caproyl, and the branched-chain isomers thereof; said groups being the acyl radicals of alkanoic acids containing fewer than 7 carbon atoms.
This application is a continuation-in-part of my copending application, Serial No. 835,416, filed August 24, 1959, and now abandoned. 7
Suitable starting materials for the manufacture of the instant compounds are the appropriately 3-oxygenated 16,17 epoxyestra 1,3,5 (10) trienes. Dehydrobromination of the 3-oxygenated l6a,175 -halohydrins, prepared by the method disclosed at J. Org. Chem. 23, 1190 (1958), affords the 5-epoxides, as typified by the reaction of 16a-bromo-3-methoxyestra-1,3,5(10) trien-l75 01 With methanolic potassium hydroxide to afford 3-methoxy 165,l75-epoxyestra-1,3,5(l0) triene. Reaction of these 5-epoxides with a hydrohalogen acid results in the instant l7a,-l65-halodydrins. One the other hand, reaction of the u-epoxides, prepared by epoxidation of the corresponding l6-dehydro derivatives with perbenzoic acid, with a hydrohalogen acid produces 175,l6cx-halohydrins of this invention. Specific examples of these processes are the reaction of hydrogen fluoride in tetrahydrofuran with 165,175-epoxy-3-methoxyestra-1,3,5 triene or with 160:,l7a-6POXY 3 methoxyestra-1,3,5(10)-triene to afiord 17a-fiuoro-3-methoxyestra-1,3,5(10)-trien-165- 01 and l75-tluoro-3-methoxyestra-1,3,5(10)-trien-16u-ol, respectively.
Oxidation of the aforementioned halohydrins, typically with chromium trioxide in pyrid'ne, results in the corresponding 17-halo 16-ketones. For example, the reaction of l7a-bromo-3-methoxyestra-1,3,5(10)-trien 165- 01 with chromium trioXide in pyridine, affords 17a-bromo- 3-rnethoxyestra-l,3,5 10) -trien-l6-one.
Reaction of the aforementioned 17-halo l6-ketones with a suitable reducing agent produces the halohydrins of this invention wherein the configurations of the halogen and hydroxy substituents are the same. Thus, treatment of 17u-bro-mo-3-methoxyestra-1,3,5(10)-trien 16 one or 175 bromo-3-methoxyestra-l,3,5(10)-trien-16-one with lithium aluminum hydride in tetrahydrofuran affords 17abromo-3-methoxyestra-1,3,5(l0) trien-l6a-ol and 175- 2 =bromo 3 methoxyestra-1,3,5(10)-trien-l6a-ol, respectively.
The 175-halo l6-ketones of this invention can be manufactured also by epimer-ization of the corresponding 17w halo compounds. This process is specifically illustrated by the reaction of 17d-bromo-3-methoxyestra 1,3,5(16)- trien-16-one with p-toluenesulfonic acid to afford 17abromo-3-methoxyestra-1,3,5(10)-trien-l6-one.
Although the 16,17 epoxy-3-hydroxyestra-1,3,5(10)- trfenes can be used as such to achieve the instant 3-hydroxy compounds, the phenolic moiety is preferably protected by a lower alkanoyl group in order to prevent any possible oxidative decomposition. Thus, 16a-bromo-3- hydroxyestra-1,3,5(10)-trien-l75-ol is reacted with methanolic potassium hydroxide to afford 165,175 epoxy-3- hydroxyestra-1,3,5(10)-triene, which is treated with a low er alkanoic ac'd anhydride in pyridine to afford the corresponding 3-(lower alkanoate). This ester can be, of course, treated as described in detail supra, to afford the 3-hydroxy compounds of this invention.
The instant 3,16-di-(lower alkanoates) are preferably manufactured by reaction of the corresponding 3,16-diols with a lower alkanoi-c acid anhydride in pyridIne. As a specific example, 175 bromo-3-hydroxyestra-1,3,5(l0)- trien-l65-o1 is treated with acetic anhydride in pyridine to yield 3,165 diacetoxy 175-bromoestra 1,3,5(10)-' triene.
On the other hand, treatment of a 3,16-diol of this invention with a limited quantity of a lower alkanoic acid anhydride in pyridine results in production of an instant 3-(lower alkanoate).
The compounds of this invention are useful as result of the'r valuable pharmacological properties. They are, for example, estrogens in consequence of their ability to promote uterine growth and to produce characteristic changes in the vaginal epithelium.
The invention will appear more fully from the examples which follow. These examples are set forth by Way of illustration only and it will be understood that the invention is not to be construed as limited in spirit or in scope of the details contained therein, as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples temperatures are given in degrees Centigrade C.). Quantities of materials are expressed in parts by weight except where otherwise noted.
Example I A solution of 6 parts of potassium hydroxide and 4.3 parts of l6ct-bromo-3-methoxyestra-1,3,5(10)-trien-l75-ol in parts of methanol is heated at reflux for about 19 hours. The solution is cooled and diluted with water, and the resulting crystalline product washed Well with water and dried. This substance is purified by adsorption on silica gel, elution with 25% benzene in hexane, and re crystallization from ether to afford pure 1 65, 175-ep0xy- 3 rnethoxyestra 1,31,5(10) triene, MP. 116-1l6.5; [a] =+1l5 (chloroform).
By substituting an equivalent quantity of 3-n-propoxy- -bro1noestra-1,3,5 (10)-trien-175-ol or 3-acetoxy-l6ocbrornoestra-l,3,5(lO)-trien--ol and otherwise proceeding according to the herein described processes, 165, 175-epoxy-3-n-propoxyestra-l,3,5(10)-triene and 165,175- epoxy-3-hydroxyestra-1,3,5(10)-triene are obtained.
Example 2 To a solution of one part of 165,175-epoxy-3-methoxyestra-1,3,5(10)-triene in 38 parts of chloroform is added at 05, 15 parts of 48% aqueous hydrobromic acid, and the mixture stirred for about 5 minutes. The chloroform layer is separated, washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness in ('10)-trien-l6,6-ol. This bromohydrin displays an infra-' red maximum at 2.77 microns.
By substituting equivalent quantities of 16,8,17/8-epoxy- 3-hydroxyestra-1,3,5 l)-triene or 165,1713-epoxy-3-npropoxyestra-l,3,5()-triene and otherwise proceeding according to the herein described processes, 17a-bromo-3- hydroxyestra-l,3,5 10) -trien-l6,8-ol and 17a-bromo-3-npropoxyestra-1,3,S(l0)-trien-l6,8-ol are obtained.
Example 3 To a solution of one part of 163,17B-epoxy-3-methoxyestra-l,3,5(10)-triene in 38 parts of chloroform is added, at 0-5 24 parts of concentrated hydrochloric acid and the mixture shaken for about minutes. The chloroform layer is separated, washed with Water, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. The residue is extracted with ether and the extract clarified by centrifugation, then evaporated to dryness in vacuo to yield 17a-chloro-3-methoxyestra- 1,3,5 (10) -trien-l6}3-ol, which exhibits a maximum in the in irared at 2.77 microns.
By substituting an equivalent quantity of concentrated hydriodic acid and otherwise proceeding according to the herein described processes, 17a-iodo-3-methoxyestra-l,3, 5(l0)-trien-16-ol, which displays an infrared maximum at 2.77 microns, is obtained.
Example 4 Example 5 To a suspension of 2.4 parts of chromium trioxide in 24 parts of pyridine is added, with stirring, a solution of 1.2 parts of 17wbromo-3-methoxyestra-1,3,5(10)-trien- 165-01 in 12 parts of pyridine. Stirring at room temperature is continued for about 3 hours, then water added and the mixture extracted with ether. The ether layer is separated, washed successively with water, dilute hydrochloric acid, water and saturated aqueous sodium chloride; then dried over anhydrous magnesium sulfate and concentrated to an oil in vacuo. This oil is adsorbed on silica gel, eluted with chloroform, and the eluate evaporated to yield an oil which crystallizes on standing. Recrystallization from ether affords pure 17a-bromo-3-methoxyestra-1,3,5 (10)-trien-l6-one, MP. 133.5-l36.5; [a] =5 (chloroform) The substitution of an equivalent quantity of 170:- chloro-3-methoxyestra-l,3,5(10)-trien-l6B-ol in the instant process results in pure 17cc-chloro-3-methoxyestra- 1,3,5(10)-trien-l6-one, M.P. 11l.1-1l2.5; [a] =49 (chloroform) Example 6 To a stirred solution of one part of lithium aluminum hydride in 70 parts of dry ether is added, at 0 over a period of about 10 minutes, a solution of 6.45 parts of 17a-bromo-3-methoxyestra-1,3,5(10)-trien-16-one in 54 parts of tetrahydrofuran. The reaction mixture is treated successively with water and excess dilute hydrochloric acid, then extracted with ether. The organic layer is separated, washed successively with water and aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and evaporated to an oil in vacuo. The residue is adsorbed on fullers earth and eluted with 40% benzene in heptane. Evaporation of the eluate afiords an oil which crystallizes on standing. Recrystallization from acetonepentane yields pure 17tx-bromo-3-methoxyestra-1,3,5 10)- tliEIl-l6cx-Ol, MP. -126.5; [a] =|7.9 (chloroform).
Example 7 A mixture of 2 parts of 17a-bromo-3-methoxyestra-1, 3,5(l0)-trien-16-one, 5 parts of p-toluenesulfonic acid, and 100 parts of acetic acid is heated at reflux for about 68 hours. The reaction mixture is diluted with water and extracted with benzene. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness at reduced pressure. A benzene solution of the residue is chromatographed on silica gel. Elution of the column with 1% ethyl acetate in benzene and concentration of the eluate to dryness aifords a solid residue which is recrystallized first from methylene chloride-methanol, then from methanol to afford 17,3- bromo-3-methoxyestra-1,3,5( lO)-trien-16-one, M.P. about 226-229"; [a] =100.
Example 8 The substitution of an equivalent quantity of 17a:- chloro-3-methoxyestral,3,5(lO)-trien 16 one in the process of Example 7 results in 17fl-chloro-3-methoxyestra-l,3,5(l0)-trien-16-one, Ml. about 211-213"; [a] =-92.
Example 9 To a stirred solution of 7 parts of lithium aluminum hydride in 700 parts of ether is added, at 5 over a period of several minutes, a solution of 15 parts of 175- bromo-3-methoxyestra-1,3,5(10)-trien-l6-one in 355 parts of tetrahydrofuran. The reaction mixture is treated successively with 50 parts of water and 10 parts of 10% aqueous sodium hydroxide, filtered through a bed of anhydrous magnesium sulfate containing a filter aid and evaporated to dryness at reduced pressure. The resulting residue is recrystallized from acetone-petroleum ether, then from petroleum ether to produce 1713-bromo-3- methoxyestra-l,3,5(l0)-trien-l6;9-ol, M.P. about 151"; [a] =+7O.
Example 10 A mixture of one part of 17a-bromo-3-hydroxyestra- 1,3,5 (10)-trien-l6p-ol, 10 parts of acetic anhydride, and 20 parts of pyridine is warmed on the steam bath to achieve homogeneity, then allowed to stand at room temperature for about 16 hours. The reaction mixture is diluted with water and extracted with ether. The organic solution is washed successively with aqueous sodium bicarbonate and water, dried over anhydrous magnesium sulfate, and evaporated to dryness in vacuo to yield 3,16,8-diacetoxy-l7ot-bromoestra-l,3,5 (10)-triene.
Substitution of an equivalent quantity of n-butyric anhydride in the instant process results in 3,l6fl-di-n-.
butyroxy-17a-bromoestra-1,3,S(10)-triene.
Example 11 Example 12 A mixture of 2 parts of 17a-bromo-3-hydroxyestra- The benzene solu-.
1,3,5()-trien-16-one, 10 parts of acetic anhydride, and 20 parts of pyridine is allowed to stand at room temperature for about hours. The reaction mixture is diluted with water and extracted with benzene. The organic layer is separated, washed successively with water and aqueous potassium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated to dryness in vacuo. The crude product can be recrystallized from aqueous ethanol to produce pure 3-acetoxy-l7a-brornoestra-1,3, 5(10)-trien-l6-one. This substance displays maxima in the infrared at 5.70 microns.
Example 13 Example 14 By substituting an equivalent quantity of 17/8-chlor0- 3-methoxyestra-1,3,S(10)-trien-l6-one and otherwise proceeding according to the procedure of Example 9, 17/8- chloro-3-methoxyestra-1,3,5(10)-trien-16fl-ol is obtained.
Example 15 The substitution of an equivalent quantity of 17a:- bromo-3-methoxyestra-1,3,5 (10) trien 165 01 or 175- chloro-3-methoxyestra-1,3,5(10)-trien-16B-ol in the process of Example 10 results in l6fl-acetoxy-l7u-bromo-3- methoxyestra-l 3, 5 10)-triene and 16B-acetoxy-17/3-chloro-3-methoxyestra-1,3,5(10)-triene.
Example 16 The substitution of one part of 16a,17a-epoxy-3-methoxyestra-l,3,5(10)-triene in the process of Example 4 results in 17,6-fluoro-3-methoxyestra-1,3,5(10)-trien-l6aol, M.P. about 74-76"; [a] =+18.
6 Example 17 The substitution of an equivalent quantity of 17afiuoro-3-methoxyestra-1,3,5(10) trien 16,3 01 or 17 3- fluoro-3-methoxyestra-1,3,5(10)-trien-16ao1 in the procedure of Example 4 affords 17a-fluoro-3-methoxyestra- 1,3,5 (10)-trien-l6-one, M.P. about 148l49 and 17B-fiuoro-3-methoxyestra-1,3,5 (10)-trien 16 one, M.P. about -156, respectively.
What is claimed is:
1. A member selected from the group consisting of compounds of the structural formulae Ki -(l3 wherein R is selected from the group consisting of hydrogen, lower alkyl, and lower alkanoyl radicals; X is a halogen atom, and Z is selected from the group consisting of carbonyl, hydroxymethylene, and (lower alkanoy1)-oxymethy1ene radicals.
17-bromo-3-methoxyestra-1,3,5 10) -trien-16-one. 1 7-ch1oro'3-methoxyestra-1,3,5 10 -t.rien-1 6-one. 17-bromo-3-methoxyestra-1,3,5(10)-trien-l6-o1. 17-chloro-3-methoxyestra-1,3,5 10) -trien-1 6-01. 17-f1uoro-3-methoxyestra-1,3,5 10) -trien-16-one. 17-fiuoro-3-rnethoxyestra-1,3,5 10 -trien- 1 6-01.
No references cited.
and
Claims (1)
1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE STRUCTURAL FORMULAE
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| US3079408A true US3079408A (en) | 1963-02-26 |
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| US3079408D Expired - Lifetime US3079408A (en) | Ig-bisoxygenated iy-haloestra- |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4016269A (en) * | 1974-08-12 | 1977-04-05 | Schering Aktiengesellschaft | 17α-HYDROXY-1,3,5(10),15-ESTRATETRAENES AND PROCESS FOR THEIR PRODUCTION |
| FR2780060A1 (en) * | 1998-06-23 | 1999-12-24 | Hoechst Marion Roussel Inc | 17-Halo-19-nor steroids useful in hormone replacement therapy |
| WO2000047603A2 (en) * | 1999-02-09 | 2000-08-17 | Schering Aktiengesellschaft | 16-hydroxyestratrienes as selective estrogens |
-
0
- US US3079408D patent/US3079408A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
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| None * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4016269A (en) * | 1974-08-12 | 1977-04-05 | Schering Aktiengesellschaft | 17α-HYDROXY-1,3,5(10),15-ESTRATETRAENES AND PROCESS FOR THEIR PRODUCTION |
| FR2780060A1 (en) * | 1998-06-23 | 1999-12-24 | Hoechst Marion Roussel Inc | 17-Halo-19-nor steroids useful in hormone replacement therapy |
| WO1999067274A1 (en) * | 1998-06-23 | 1999-12-29 | Hoechst Marion Roussel | Novel 17-halogenated 19-nor steroids, method and intermediates for preparing same, use as medicines and pharmaceutical compositions containing same |
| JP2002518516A (en) * | 1998-06-23 | 2002-06-25 | ヘキスト・マリオン・ルセル | Novel 17-halogenated-19-norsteroids, their preparation and intermediates, their use as medicaments and pharmaceutical compositions containing them |
| US6423700B1 (en) | 1998-06-23 | 2002-07-23 | Aventis Pharma S.A. | 17-halogenated 19-nor steroids, method and intermediates for preparing same, use as medicines and pharmaceutical compositions containing same |
| EA003325B1 (en) * | 1998-06-23 | 2003-04-24 | Хехст Марион Руссель | Novel 17-haligenated 19-nor steroids, method and intermediates for preparing same, use as medicines and pharmaceutical compositions containing same |
| WO2000047603A2 (en) * | 1999-02-09 | 2000-08-17 | Schering Aktiengesellschaft | 16-hydroxyestratrienes as selective estrogens |
| WO2000047603A3 (en) * | 1999-02-09 | 2001-08-02 | Schering Ag | 16-hydroxyestratrienes as selective estrogens |
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